Infertility afflicts about 5 million American women in the United States (about 10-15%). Many factors may account for infertility including abnormalities of the uterus (such as fibroids); ovarian dysfunction; endometriosis (the presence of uterine tissue in ectopic locations such as the ovaries); scar tissue from previous surgery; thyroid problems or other hormonal imbalances; sexually transmitted diseases or other infections, or unexplained infertility (idiopathic infertility). One primary cause of infertility is chronic anovulation due to hypoestrogenic hypogonadism. This disorder is associated with serum estrogen in the post-menopausal range, normal to low follicle-stimulating hormone (FSH), which causes irregular menses or amenorrhea. These patients usually have normal prolactin levels. A second cause of infertility is attributed to hypergonadotropic hypogonadism. These patients have elevated FSH and postmenopausal estrogen levels. This category includes patients with premature ovarian failure.
Other causes of infertility include hyperprolactinemia, which results in low levels of luteinizing hormone (LH) and FSH, resulting in a failure of the positive feedback response of gonadotropin secretion induced by estrogen; hypothyroidism, which results in hyperprolactinemia; hypothalamic-pituitary dysfunction, caused by low body fat due to excessive weight loss from strenuous exercise, eating disorders, or tumors; luteal phase defects (insufficient progesterone production by the ovary or poor response of the uterus to progesterone); and androgenization, e.g., polycystic ovarian syndrome (PCOS). PCOS is characterized by menstrual disturbances (oligomenorrhea or dysfunctional uterine bleeding), increased male pattern hair growth (hirsutism), acne, alopecia, obesity, and infertility (Blankstein et al., Infertility. 1998; 83: 97-102).
Still additional causes of anovulation include resistant ovary syndrome, autoimmune oophoritis, and premature ovarian failure. Resistant ovary syndrome is characterized by amenorrhea, endogenous hypergonadotropinemia, and resistance to exogenous gonadotropins. Histologically there is an almost complete absence of developing follicles. The exact cause is unknown, and there are several theories including a deficiency of FSH and LH receptors in the ovary, the presence of antibodies to gonadotropin receptors, and a postreceptor defect. Galactosemia not infrequently accompanies resistant ovary syndrome and may be a causative factor. Autoimmune oophoritis is characterized by inflammation of ovaries resulting in their destruction, atrophy, and fibrosis with a loss of fertility and ovary hormonal production. It leads to premature ovarian failure (POF) in 10 percent of cases. Women with POF have premature menopause before 40 years of age.
Lastly, lifestyle habits such as heavy alcohol, and/or caffeine consumption, smoking, or illicit drug use is also associated with decreased fertility.
Infertility is typically treated with ovulation induction agents, commonly referred to as fertility drugs. Exemplary ovulation induction agents include human menopausal gonadotropins (hMG), human chorionic gonadotropin (hCG), clomifene, FSH, luteinizing hormone (LH), gonadotropin-releasing hormone (GnRH) and analogs thereof, and combinations of the foregoing (Derman et al., Drug Safety. 1994; 11: 408-21). These drugs work through different mechanisms, depending on the cause or suspected cause of the infertility. For example, bromocriptine, a dopamine agonist, decrease prolactin secretion in women with hyperprolactinemia, while other agents such as clomifene increase FSH production.
In addition, in vitro fertilization (IVF) is routinely used for all kinds of infertility. IVF involves a process where mature eggs are removed from the ovaries, fertilized with sperm in a laboratory dish, and then the resulting embryos are implanted into the uterus within several days. Prior to egg removal, ovaries are stimulated using fertility drugs such as Pergonal® (hMG) or Metrodin® (a combination of FSH and LH). Several variations of IVF include gamete intrafallopian transfer (GIFT), zygote intrafallopian transfer (ZIFT), Intracytoplasmic sperm injection (ICSI), and intrauterine insemination. In the latter, a purified fraction of highly motile sperm is placed either in the cervix or high in the uterine cavity following ovarian hyperstimulation (also known as “controlled ovarian stimulation” or “ovulation induction”) with fertility drugs. Luteal phase defects are more likely to occur with the higher estrogen levels produced during ovulation induction, either alone or with IVF techniques.
Ovarian Hyperstimulation Syndrome
Ovarian Hyperstimualtion Syndrome (OHSS) is a complication of ovarian induction therapy that involves the use of gonadotropin hormones, such as hCG, during fertility treatments or prior to IVF and related procedures. Three grades of OHSS can be distinguished by clinical and sonographic criteria. Mild OHSS is associated with mild abdominal discomfort, including diarrhea, and the ovaries are usually less than 5 cm in diameter on sonographic examination. With moderate OHSS, the ovaries measure between 5 and 10 cm, and in the severe form, the ovaries are greater than 10 cm in diameter. Severe OHSS is characterized by the presence of free intraperitoneal fluid (ascites) due to increased vascular permeability. Pleural effusions, hypotension, and oliguria have also been described. The patient also may have fluid and electrolyte disturbances and is at increased risk for torsion of the enlarged ovaries. Severe OHSS occurs in fewer than 2% of patients.
Hypotension results from extravasation of protein-rich fluid and contraction of the vascular volume, oliguria/anuria from reduced renal perfusion due to decreased vascular volume and/or tense ascites, and pulmonary indications from an elevated diaphragm and/or hydrothorax. Risk of thromboembolism is increased as a result of hemoconcentration, diminished peripheral blood flow, and inactivity due to abdominal distension and pain. Life-threatening complications of OHSS include renal failure, adult respiratory distress syndrome (ARDS), hemorrhage from ovarian rupture, and thromboembolism.
Sonographic and laboratory findings aid in predicting which patients are more likely to develop. Estradiol levels are the most accurate indicator. A value of 4000-6000 pg/mL or greater at the time of hCG administration correlates with a higher risk of developing the syndrome. In addition the development of more than eight follicles in an ovary also correlates with an increased risk for OHSS. Other risk factors for OHSS include The following factors increase the risk independently for developing ovarian hyperstimulation syndrome (OHSS): young age; low body weight; polycystic ovary syndrome (PCOS); high doses of exogenous gonadotropins; high absolute or rapidly rising serum estradiol levels; and previous episodes of OHSS.
Treatment and Prevention. Treatment of mild OHSS typically is the use of an oral analgesic and avoidance of intercourse. For moderate OHSS, treatment consists of more potent analgesics, antiemetics, and frequent monitoring such as by regular sonograms, daily weight monitoring, and frequent serial laboratory determinations of hematocrit, electrolytes, and serum creatinine. In addition, fluid intake and strenuous exercise should be limited. Hospitalization is commonly required for monitoring and treatment of patients having severe OHSS.
For those deemed to be at a high risk for OHSS, lowering the hCG doses by about half is warranted for infertility treatment. In addition, subsequent supplementation with progesterone as opposed to addition of hCG may further reduce the risk of OHSS. Administration of intravenous albumin (25%) is also used when estradiol levels are elevated, or there is a history of prior OHSS, although studies of its efficacy have been mixed, and albumin treatment risks exacerbation of ascites, allergic reactions, and virus/prion transmission.
Although caused primarily by ovulation induction during fertility treatment, OHSS also has been reported in patients having mutations in the follicle-stimulating hormone (FSH) gene Smits et al., New Engl. J. Med. 2003. Volume 349:760-766).
In summary, there remains a need in the art for effective therapies to prevent and treat OHSS.